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Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4‐phosphatase‐1
Author(s) -
Ivetac Ivan,
Gurung Rajendra,
Hakim Sandra,
Horan Kristy A,
Sheffield David A,
Binge Lauren C,
Majerus Philip W,
Tiganis Tony,
Mitchell Christina A
Publication year - 2009
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2009.28
Subject(s) - protein kinase b , pleckstrin homology domain , microbiology and biotechnology , inositol , phosphorylation , biology , phosphatase , cell growth , pten , signal transduction , pi3k/akt/mtor pathway , chemistry , receptor , biochemistry
Akt is a crucial phosphoinositide 3‐kinase (PI(3)K) effector that regulates cell proliferation and survival. PI(3)K‐generated signals, PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 , direct Akt plasma membrane engagement. Pathological Akt plasma membrane association promotes oncogenesis. PtdIns(3,4)P 2 is degraded by inositol polyphosphate 4‐phosphatase‐1 (4‐ptase‐1) forming PtdIns(3)P; however, the role of 4‐ptase‐1 in regulating the activation and function of Akt is unclear. In mouse embryonic fibroblasts lacking 4‐ptase‐1 ( −/− MEFs), the Akt‐pleckstrin homology (PH) domain was constitutively membrane‐associated both in serum‐starved and agonist‐stimulated cells, in contrast to +/+ MEFs, in which it was detected only at the plasma membrane following serum stimulation. Epidermal growth factor (EGF) stimulation resulted in increased Ser 473 and Thr 308 ‐Akt phosphorylation and activation of Akt‐dependent signalling in −/− MEFs, relative to +/+ MEFs. Significantly, loss of 4‐ptase‐1 resulted in increased cell proliferation and decreased apoptosis. SV40‐transformed −/− MEFs showed increased anchorage‐independent cell growth and formed tumours in nude mice. This study provides the first evidence, to our knowledge, that 4‐ptase‐1 controls the activation of Akt and thereby cell proliferation, survival and tumorigenesis.